PROJECT SUMMARY Diabetes mellitus, a heterogeneous group of diseases characterized by hyperglycemia, affects over 29 million individuals in the United States and 415 million worldwide and is a leading cause of cardiovascular disease, blindness, end-stage renal disease and death. Maternal pre-existing or gestational diabetes is also associated with risk for poor pregnancy outcomes. Highly penetrant genetic forms of diabetes including maturity onset diabetes of the young (MODY), neonatal diabetes, and syndromes that comprise both diabetes and developmental and intellectual disabilities account for at least 1% of diabetes, or over 290,000 cases nationwide. Distinguishing these genetic forms of diabetes from type 1 (T1DM) and type 2 diabetes (T2DM) demonstrably improves glucose control and quality of life by enabling replacement of invasive insulin treatment and/or ineffective oral treatment with less invasive and more efficacious etiology-based oral or dietary treatment for the patients and their affected family members. In some cases, the individualized treatment can ameliorate neurological dysfunction. However, a recent U.S. population-based study provided evidence that only 6% of MODY in diabetic individuals age 20 and younger was properly diagnosed as such, with a likely even lower percentage in adults. There are several barriers to improving the diagnosis rate, including lack of awareness, clinical overlap with other diabetes types, expense of testing, genetic heterogeneity and predominance of rare variants. With the advent of next generation sequencing techniques, testing is becoming increasingly feasible and cost-effective, but for its true potential to be realized, a systematic process for the pooling, annotation and curation of variants is needed. We are a group of investigators from academic and non-academic institutions around the world (University of Maryland School of Medicine, University of Chicago, Northshore University Health System, and Geisinger Health System in the United States; University of Exeter in the United Kingdom; and University of Auckland in New Zealand) who are developing innovative approaches to identifying, diagnosing and promoting individualized therapy for monogenic diabetes. Together we will develop an approach to centralize the annotation and curation of variants in genes known to be implicated in monogenic diabetes; develop and implement a sustainable process for systematic consensus review of monogenic diabetes variants for pathogenicity and submission to ClinVar; and lay the groundwork for a Diabetes Clinical Domain Working Group that will enable the use of genetic tools in the diagnosis and management of more complex forms of diabetes as the field matures.